It is well known that vascular stiffness increases with aging, yet the mechanisms involved are poorly understood, potentially due, in part, to lack of appropriate models. Indeed, the majority of research in aging has been conducted in rodent models or in humans with associated diseases of aging, e.g., diabetes or atherosclerosis. The primate model is unique because it is phylogenetically closer to humans, yet does not have associated diseases of aging. Over the past funding period, we have developed this primate model and have uncovered novel preliminary data supporting the renewal application. Our preliminary data indicate that female monkeys appear relatively protected from the vascular changes associated with aging compared with males. There are major gender differences observed in the composition of the vascular wall with aging and also in response to sympathomimetic amines. Accordingly, one important theme in this proposal includes examination of gender differences during aging. We will examine three hypotheses 1) Vascular stiffness increases in old male monkeys, but is relatively protected in old female monkeys. However, importantly, our hypothesis is that increases in vascular stiffness cannot be ascribed entirely to changes in collagen and elastin. Therefore, we propose two novel hypotheses: a.) that one mechanism of increased vascular stiffness with age involves caveolin and microtubules polymerization; and B.) that in part the increase in vascular stiffness with age resides at the level of the smooth muscle cell. For these studies, vascular smooth muscle stiffness will be assessed using an atomic force microscope; 2) Differences in the pattern of the expression of genes could explain the gender differences involved in the development of vascular stiffness; and 3) Gender differences must exist in the pattern of expression of proteins that could explain the differences involved in the development of vascular stiffness. These hypotheses and aims will be investigated using a multidisciplinary approach to maximally utilize this novel primate model.